The impact of postoperative adjuvant therapy on EGFR-mutated stage IA lung adenocarcinoma with micropapillary pathological subtypes

Background Micropapillary (MPP) adenocarcinoma is considered one of the most aggressive pathological types of lung adenocarcinoma (LADC). This retrospective study aimed to evaluate the prognostic significance and benefit of postoperative adjuvant therapy (PAT) in stage IA LADC patients with different proportions of MPP components. Materials and methods We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019. In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH). The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination. Results Overall, 505 (TPMN, n = 375; TPML, n = 92; TPMH, n = 38) patients harboring EGFR mutations were enrolled in the study. Male sex (P = 0.044), high pathological stage (P < 0.001), and MPP pathological subtype (P < 0.001) were more frequent in the TPM-positive (TPMP) group than in the TPM-negative (TPMN) group. Five-year disease-free survival (DFS) rates were significantly lower in the TPMP group than in the TPMN group (84.5% vs. 93.4%, P = 0.006). In addition, patients with high proportions (greater than 10%) of MPP components had worse overall survival (OS) (91.0% vs. 98.9%, P = 0.025) than those with low proportions (5%≤ TPM ≤ 10%). However, postoperative EGFR tyrosine kinase inhibitors (TKIs) or adjuvant chemotherapy (ACT) cannot improve DFS and OS between EGFR-mutated patients with different proportions of MPP components. Conclusion MPP was related to earlier recurrence and shortened survival time, even in stage IA. Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-024-03429-y.


Materials and methods
We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019.In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH).The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination.

Background
For patients with early-stage non-small cell lung cancer (NSCLC), surgery remains the most promising treatment [1].However, even after complete surgical resection, there is still a risk of cancer recurrence and distant metastasis [2,3].Recent findings from the ADAURA trial have shown that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve DFS duration by approximately 18 months in stage IB lung adenocarcinoma (LADC) patients with EGFR mutations [4].However, the use of adjuvant therapy after surgery for EGFR-mutated patients with stage IA NSCLC is still not supported by sufficient evidence.
Many studies have shown the effect of the presence of a micropapillary (MPP) subtype on a poorer prognosis, even in stage I LADC patients [5][6][7][8].Patients with a significant MPP component (equal to or greater than 5%) in their surgical specimen are considered at high risk for cancer recurrence and metastasis [9].While adjuvant therapy is not routinely recommended for stage IA NSCLC patients in current clinical practice [10], more aggressive treatment approaches are needed to control disease progression in MPP-predominant cases.
In this study, we aimed to explore the clinicopathological characteristics and survival outcomes of EGFR-mutated stage IA LADC patients with different proportions of MPP components.Specifically, we investigated whether these high-risk patients in the early stage can benefit from EGFR-TKIs or adjuvant chemotherapy (ACT).By understanding the potential benefits of postoperative adjuvant treatment (PAT) in this specific subgroup, we hope to provide insights that can improve their overall prognosis and guide treatment decisions.

Study design and population
From August 2012 to December 2019, we retrospectively reviewed all patients who underwent complete resection and histologically confirmed stage IA LADC at the First Affiliated Hospital of Guangzhou Medical University, and all EGFR-mutant patients were included in this study.The exclusion criteria of this study were as follows: (1) patients with multiple primary carcinomas; (2) patients whose tumor tissue for immunohistochemistry and genetic testing was insufficient; (3) patients with incomplete clinical data or follow-up information; (4) EGFR wild-type patients.

Data collection
Data on patient demographics were collected from the medical records, including age, sex and smoking history.Occasional gaps in the interview records led to certain cases being classified as unknown for smoking history.Cancer information was documented in pathological reports and included tumor laterality, resection type, T stage and EGFR mutation status.The type of surgical resection was categorized into lobectomy or sublobectomy, which included segmentectomy and wedge resection.Tumor staging was classified according to the eighth edition of the TNM classification of the International Association for the Study of Lung Cancer.Pathological types and EGFR mutation status were derived from surgical specimens.EGFR mutations were identified by either next generation sequencing or the polymerase chain reaction (PCR) method.
Postoperative follow-up chest CT scans were performed every 3 to 6 months for the first two years and annually thereafter until progressive disease or death.The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination.The primary endpoint of this study was the 5-year DFS, defined as the duration from the initiation of operation to the first recurrence or death.The secondary endpoint was overall survival (OS), defined as the duration from the initiation of operation to death from any cause.To gather data on patients without recorded survival status in the postoperative medical records, we conducted telephone interviews to assess their overall well-being and disease status.

Histologic evaluation
All specimens were routinely fixed in formalin and stained with hematoxylin and eosin (HE).Two pathologists together reviewed an average of 8 (range 4-12) slides per patient using a multiheaded microscope.Tumors were classified into 5 distinctive subtypes based on the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification criteria as (1) acinar, (2) lepidic, (3) solid, (4) micropapillary (MPP), (5) papillary.The ratio of each histological component was calculated in 5% increments.The largest proportion of a combination of histological patterns was identified as the predominant subtype, and the lowest limit for the predominant subtype was set at 30%.

Conclusion
MPP was related to earlier recurrence and shortened survival time, even in stage IA.Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy.Keywords Lung adenocarcinoma, Micropapillary, EGFR, Adjuvant therapy, Prognosis (2024) 22:235 In terms of the proportion of MPP components (TPM), patients were divided into two groups: TPM-negative (TPMN, tumors without MPP subtype) and TPM-positive (TPMP, tumors with MPP subtype).Then, in the defined positive group, tumors with 5% ≤ TPM ≤ 10% were classified as TPM-low (TPML), and those with TPM greater than 10% were classified as TPM-high (TPMH).Lung cancer staging was performed for all patients according to the eighth tumor node metastasis (TNM) staging classification.

Statistical analysis
The χ2 test was used to compare the characteristics of patients for categorical variables.The Pearson test was used to determine the correlation.DFS and OS curves were plotted by the Kaplan-Meier method, and the logrank test was used to evaluate the differences among the subgroups.Univariate and multivariate analyses were used to assess the effect of the covariates on DFS and OS.The HR and 95% CI were estimated using the Cox proportional hazards model.The variables with P < 0.05 on univariate analysis were used as the input variables for the multivariate analysis.All statistical analyses were carried out using SPSS software, version 23.0 (IBM Corporation, Armonk, NY, USA) and R version 4.3.1 (R Development Core Team, Vienna, Austria).Statistical significance was considered as P values less than 0.05.
The clinical baseline characteristics of the 505 patients with the MPP subtype were compared in Table 1.The presence of MPP patterns was significantly associated with male sex (P = 0.044) and high pathological T stage (P < 0.001).Meanwhile, patients in the TPMP group were more willing to receive adjuvant therapy (P < 0.001), but still had a higher rate of recurrence (P = 0.001).A total of 45 recurrence events were recorded among the 505 patients analyzed (8.9%).In addition, 24 of those occurred in the TPMN group (6.4%), and 21 occurred in the TPMP group (16.2%).
Furthermore, we divided 130 patients into low and high percentage groups (Table 2).Patients in the TPMH group had a higher proportion of MPP patterns (P = 0.010) and an increased mortality risk (P = 0.033).However, there were no significant differences in other parameters among the TPML and TPMH groups.
Univariable and multivariable analysis were used to explore the factors affecting DFS and OS for EGFRmutated stage IA patients, adjusting for age, sex, smoking history, tumor laterality, resection type, T stage, TPM group, predominant subtype, and EGFR mutation status (Table 3).Notably, TPM greater than 10% was identified as an independent prognostic factor for both DFS (P = 0.013) and OS (P = 0.017).However, a low proportion of MPP components was associated only with a shortened DFS (P = 0.047).

Discussion
This retrospective study reports real-world data for the clinicopathological characteristics and survival outcomes of EGFR-mutated stage IA LADC patients.Importantly, it demonstrates that the high proportions of the MPP subtype significantly influence prognostic outcomes.Since a new histological classification of LADC was proposed by IASLC/ATS/ERS, the impact of the MPP component on the survival of early lung cancer had attracted more attention.Previous research has proven that earlystage lung tumors with the MPP subtype show a higher more frequency of lympho-vascular invasion (LVI) and spread through air spaces (STAS) [10][11][12][13].But there are few reports emphasizing the prognostic value of the percentages of MPP components.Qian et al. [14] conducted an analysis of stage IB LADC patients and found that the survival of the SMPP (solid/micropapillary-predominant) group was even poorer than that of the SMPM (solid/micropapillary-minor) group.As a result, according to TPM, we divided patients into three different subgroups, including TPMN (tumors without MPP subtype), TPML (tumors with 5% ≤ TPM ≤ 10%), and TPMH (TPM greater than 10%).In our study, the survival analyses have demonstrated that DFS was significantly poorer in patients with the presence of an MPP pattern (P = 0.006), and the OS trend was worse in the high proportion of MPP subtype group (P = 0.025).Meanwhile, multivariable analyses identified TPM greater than 10% as an independent prognostic factor for both DFS (P = 0.013) and OS (P = 0.017).
In the entire study cohort, the role of targeted therapy failed to be detected.Previous studies concluded the prognostic implication of EGFR mutations in resected NSCLC cases [15][16][17][18][19]. Ito et al. [20] demonstrated that the ratio of EGFR mutations and the risk of recurrence vary among histological subtypes in pN0M0 LADC.Exploring the clinicopathological characteristics of EGFR mutations is essential for lung cancer treatment.It is well known that MPP components of 5% or higher are a potential pathological marker for poor prognosis [8,9,21,22].Additionally, some studies have found that the frequency of MPP is higher in EGFR mutations [23][24][25].Although biologically aggressive, OS is generally prolonged after receiving EGFR-TKIs [12,13,26].However, the efficacy of TKIs is inconsistent among different patients, which may result from histologic features.In summary, histological subtypes of LADC with EGFR mutations can help predict the prognostic impact and therapeutic effect of TKIs.Although the National Comprehensive Cancer Network (NCCN) guideline suggest that PAT may be considered in stage IB patients with high-risk factors [27], the rationality of PAT in stage IA patients with MPP components remains controversial.Wang et al. [28] analyzed 152 stage IA LADC patients with MPP-predominant disease and revealed a better OS benefit of chemotherapy in subgroups stratified according to EGFR mutation status.However, the data excluded patients receiving targeted therapy.Yucheng et al. [29] reported that no significant difference was observed in MPP pattern stage IA patients who received postoperative chemotherapy.Regarding treatment efficacy, our study found that patients with MPP patterns did not benefit from PAT, regardless of whether they received EGFR-TKIs or chemotherapy.Kaplan-Meier curves further confirmed that patients with different proportions of MPP components had comparable prognoses whether they received PAT or not.These findings suggest that current PAT strategies may not be sufficient to improve outcomes in EGFR-mutated stage IA LADC patients with MPP patterns.The lack of significant benefit from EGFR-TKIs and chemotherapy in this subgroup indicates the need for alternative therapeutic approaches or the identification of novel biomarkers to better stratify patients who might benefit from specific treatments.Therefore, we need closer surveillance for stage IA patients in this high-risk subgroup.Meanwhile, whether EGFR-mutated stage IA patients with MPP components can obtain survival benefits from targeted therapy or even chemotherapy needs further research based on a large sample size in the future.
There were some limitations to this study.First, it was a single-institution retrospective study, and incomplete data were inevitable.Additionally, the regimen selection and postoperative adjuvant decision were based on physician preference rather than randomization.Therefore, prospective multicenter clinical trials are warranted to validate the results in the future.

Conclusion
The proportion of MPP components is a significant marker of poor prognosis in EGFR-mutated patients with stage IA LADC.In these patients, future clinical trials are warranted to evaluate the role of EGFR-TKIs and adjuvant chemotherapy.

Fig. 3
Fig. 3 Kaplan-Meier survival curves for (A and C) disease-free and (B and D) overall survival according to the PAT in the TPMN (A and B) and TPMP (C and D) groups.PAT, postoperative adjuvant treatment; non-PAT, observation; TPMN, tumors without micropapillary (MPP) subtype; TPMP, tumors with MPP subtype

Table 1
Clinical characteristics of 505 EGFR-mutated stage IA LADC patients with the MPP subtype

Table 2
Clinical characteristics of 130 EGFR-mutated stage IA LADC patients with different proportions of the MPP subtype

Table 4
Clinical characteristics of 505 EGFR-mutated stage IA LADC patients with different treatments